Resuscitation after cardiac arrest (CA) entails significant risk of coma or disorders of consciousness resulting in poor neurological outcome. There is an acute need to monitor the brain function during and after resuscitation to optimize intervention and improve outcome. Our previous studies developed electrophysiological markers of post-CA brain injury, including quantitative EEG (qEEG) and quantitative evoked potentials (qEP), and their relationship to outcome and neurological deficits. Further, we demonstrated benefits of therapeutic hypothermia using these objective means. We discovered quantitative methods to track neurological injury from CA and patterns of electrical rhythms associated following resuscitation, such as burst suppression, and utilized these novel tools to demonstrate electrophysiological recovery and enhanced neurological outcome assisted by therapeutic hypothermia. The central hypothesis for this renewal is that recovery of cortical function has both cortical and subcortical origins and arousal from coma and recovery can be facilitated through hypothermic protection and pharmacological stimulation of both cortical and subcortical structures, and guided using quantitative electrophysiological markers. The specific aims are: 1) To discover clinically relevant, quantitative cortical electrophysiological markers o arousal from coma. 2) To discover changes in cortical-subcortical neurological signals and their coupling after resuscitation. 3) To establish the neuroprotective effects of therapeutic hypothermia assessed through restoration of cortical electrophysiological function and cortical-subcortical network connectivity. 4) To promote arousal from coma through pharmacologic intervention by Orexin-A infusion and resulting stimulation of cortical-subcortical network connectivity. 5) To translate this research into an objective feedback system and optimization of delivery of titrated therapeutic hypothermia for neuroprotection and pharmacological arousal by Orexin-A infusion. CA results in hundreds of thousands of deaths each year and, even for survivors, the outcome remains dismal. Our multi-faceted approach will result in mechanistic understanding of arousal, means of monitoring cortical function, and treatments to accelerate recovery of cortical function. Starting with direct multi-unit recordings of cortical and subcorticl components of the arousal system, we will provide mechanistic understanding of arousal and successful restoration after resuscitation. Further, our qEEG and qEP based monitoring approaches will result in clinically relevant, translatable monitoring of interventions, both hypothermia and pharmacological. Our research will thus result in a comprehensive development of real-time neurophysiologic monitoring technology to optimize treatment options. Upon validation, the proposed quantitative, neuroelectrophysiology-guided optimization of TH/Orexin-A delivery should be applicable to monitoring patients and guiding clinical management.